rs139499540

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2

The NM_000702.4(ATP1A2):c.1262G>A(p.Arg421Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,611,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R421R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ATP1A2
NM_000702.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

ATP1A2 (HGNC:800): (ATPase Na+/K+ transporting subunit alpha 2) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]

ATP1A2 links:

ATP1A2 (HGNC:):

ATP1A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A2. . Gene score misZ 4.7713 (greater than the threshold 3.09). Trascript score misZ 6.824 (greater than threshold 3.09). GenCC has associacion of gene with fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, alternating hemiplegia of childhood, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, familial or sporadic hemiplegic migraine, alternating hemiplegia of childhood 1, developmental and epileptic encephalopathy 98, migraine, familial hemiplegic, 2.

BP6

Variant 1-160129025-G-A is Benign according to our data. Variant chr1-160129025-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000118 (18/152282) while in subpopulation AFR AF= 0.000361 (15/41542). AF 95% confidence interval is 0.000222. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A2	NM_000702.4 linkuse as main transcript	c.1262G>A	p.Arg421Gln	missense_variant	10/23	ENST00000361216.8	NP_000693.1	P50993A0A0S2Z3W6
ATP1A2	XM_047421286.1 linkuse as main transcript	c.371G>A	p.Arg124Gln	missense_variant	3/16		XP_047277242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ATP1A2	ENST00000361216.8 linkuse as main transcript	c.1262G>A	p.Arg421Gln	missense_variant	10/23	1	NM_000702.4	ENSP00000354490.3	P50993
ATP1A2	ENST00000392233.7 linkuse as main transcript	c.1262G>A	p.Arg421Gln	missense_variant	10/23	5		ENSP00000376066.3	B1AKY9
ATP1A2	ENST00000447527.1 linkuse as main transcript	c.392G>A	p.Arg131Gln	missense_variant	3/16	2		ENSP00000411705.1	H0Y7C1
ATP1A2	ENST00000472488.5 linkuse as main transcript	n.1365G>A		non_coding_transcript_exon_variant	10/20	2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000529

AC:

AN:

245876

Hom.:

AF XY:

0.0000376

AC XY:

AN XY:

132822

show subpopulations

Gnomad AFR exome

AF:

0.000316

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000166

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1459138

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

725580

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000118

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000650

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Migraine, familial hemiplegic, 2;C3549447:Alternating hemiplegia of childhood 1;C5562015:Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies;C5562017:Developmental and epileptic encephalopathy 98

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 11, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2023

Observed in the heterozygous state in an individual with younger-onset apparently sporadic small vessel disease stroke (Tan et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18184292, 31719132) -

Familial hemiplegic migraine

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.1

L;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.63

Sift

Benign

0.051

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.78

P;P

Vest4

0.81

MVP

0.97

MPC

1.2

ClinPred

0.10

GERP RS

4.1

Varity_R

0.38

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over